Summary: Tropomyosin (TM) is an actin-binding protein which plays an important role in the maintenance of the non-transformed phenotype. The levels of the high molecular weight isoforms of tropomyosin are significantly down regulated in virtually every cancer cell line or tumor tissue. Forced re-expression of tropomyosin in ras-transformed or src-transformed cancer cell lines restores the normal phenotype of these cells. It is unclear how TM suppresses the transformed phenotype and how TM is down regulated in cancer cells. Our research tries to find answers to the following questions. 1) How does TM suppress the transformed phenotype of ras-transformed cells? Preliminary data suggest that TM may inhibit the translocation of transcription factors into the nucleus. Current research tries to further elucidate the mechanism of action of TM. 2) How is TM down regulated in ras-transformed cells? We have recently shown that the loss of TM is induced by the activities of the small GTPase Ras and its downstream effector Raf. However, it appears that the serine/threonine kinase Raf does not mediate its effects directly by the activation of its only known substrate MEK. We have demonstrated that the scaffold protein Kinase Suppressor of Ras (KSR) plays an important role in the regulation of TM expression in tumor cells. Current research tries to further elucidate the mechanism by which KSR restores TM expression. 3) How do TM and KSR affect gene expression? Both TM and KSR suppress tumor growth and induce restoration of stress fibers, cell flattening, loss of serum and anchorage independence, and decreased growth of tumors in vivo. We have shown that both molecules alter gene expression in tumor cells. Future research will try to elucidate the gene expression profiles of tumor cells that overexpress either TM or KSR using micro array technology. 4) Screen for drugs which upregulate TM expression The loss of TM appears to be an essential event in tumorigenesis. Drugs that increase TM expression may be potent anti-cancer agents. Future research aims at the development of screens for drugs which will enhance TM promoter activity in a luciferase-reporter assay.